Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide

OBJECTIVE: We sought to determine the safety and acceptability of vaginal gel formulation PC-503 among low risk, abstinent women. The active ingredient was 2% pharmaceutical grade lambda carrageenan, a sulphated polymer that is generally recognised as safe by the US Food and Drug Administration. METHODS: 35 women in five sites applied 5 ml of the PC-503 gel vaginally once a day for 7 days while abstaining from sexual intercourse. Visual vaginal examinations were performed on days 1, 4, and 8. STI testing and vaginal pool Gram stain preparations were done on days 1 and 8. Participants were asked about product acceptability. RESULTS: 34 of the 35 women enrolled completed 7 days' use. Following product use, five reported mild symptoms including "bladder fullness," "genital warmth," or discomfort, and lower abdominal pain, and one had moderate pale yellow cervical discharge. Using the Nugent criteria, three women had bacterial vaginosis (BV) before and after use; three had BV before but not after, and two had BV after but not before. Most of the women found PC-503 to be pleasant or neutral in feel and smell and considered extra lubrication to be an advantage; however, one third found it to be messy. CONCLUSIONS: Vaginal use of PC-503 gel did not cause significant adverse effects in a small number of low risk, sexually abstinent women. Further testing in larger numbers of sexually active women is planned. A smaller volume of gel may be more acceptable to some women.     

Safety trial of the vaginal microbicide cellulose sulfate gel in HIV-positive men

OBJECTIVE: Cellulose sulfate (CS) is a promising vaginal microbicide. Because men will be exposed to the microbicide when engaging in vaginal intercourse, safety and acceptability need to be assessed in men. DESIGN: This randomized double-blind phase I study assessed the safety and acceptability of seven consecutive daily doses of CS versus KY Jelly in 36 HIV-positive men. RESULTS: No new or worsening of existing genital findings were observed during the follow-up examination. Mild genital symptoms were reported in 42% of CS users (itching, burning, tingling, testicular pain, dysuria, and warm or cold feeling) and 8% of KY Jelly users. CONCLUSION: CS gel applied to the penis was well tolerated in this HIV-positive male population. The itching and burning symptoms were not severe and can be explained by the preservative benzyl alcohol present in the CS gel.     

Trypan blue staining to determine vaginal exposure in two types of plastic vaginal applicators containing two different microbicide formulations

ABSTRACT:: Dye staining of applicators has been shown to be a reliable and objective method to test vaginal insertion in clinical microbicide trials, but different plastics, dyes, and product formulations may impact the accuracy of this method. Reportedly used applicators returned from 3 clinical trials were stained with 1% trypan blue. In a phase 1 study (VivaGel), using gel-filled HTI polypropylene applicators, 1271 (97%) of applicators stained positive. In a phase 1 and a phase 2a study (LACTIN-V) using linear low-density polyethylene applicators to deliver a dry powder formulation, 57 (95%) and 135 (86%) tested positive, respectively. Dye staining of vaginal applicators is an objective low-cost measure suitable for low-resource settings.     

Phase I safety trial of two vaginal microbicide gels (Acidform or BufferGel) used with a diaphragm compared to KY jelly used with a diaphragm

OBJECTIVES: To assess the safety and acceptability of 2 vaginal microbicide gels (Acidform and BufferGel) used with a diaphragm compared to KY Jelly used with a diaphragm among low-risk, sexually abstinent women. STUDY DESIGN: Eighty-one women enrolled in a randomized, masked, phase I safety study using a diaphragm with Acidform, BufferGel, or KY Jelly for 6 to 10 hours nightly for 14 nights. Physical examination, colposcopy, and lab studies were performed after 1 and 2 weeks of use. Diaries and questionnaires were used to assess user acceptability. RESULTS: Sixty-nine participants (85%) completed the study. Safety and acceptability appeared similar among the 3 study groups and no serious adverse events related to the study products were reported. Adverse events were mild and anticipated. CONCLUSIONS: Acidform and BufferGel compared to KY Jelly, when used with diaphragm daily for 14 days, appeared to be safe and acceptable in a small study of low-risk abstinent women.     

A dose-ranging phase I study of dextrin sulphate, a vaginal microbicide, in HIV-negative and HIV-positive female volunteers

DESIGN: This phase I dose-ranging study of 2 weeks of twice-daily dextrin sulphate (DS), a sulphated polymer with in vitro activity against HIV, was designed in 2 parts. Part A was a randomized, placebo-controlled, double-blind, 3-arm trial (DS4%, DS1%, placebo) in HIV-negative women. In part B, HIV-positive women received DS4% and HIV-negative women were randomized to DS4% or no gel. RESULTS: One hundred women were enrolled from 2 sites (London and Antwerp): DS4% (n = 50, 20 of whom were HIV-positive), DS1% (n = 20), placebo (n = 10) and no gel (n = 20). There were no withdrawals related to adverse events and no cases of epithelial disruption. Spotting was reported by 24 women and numbers were significantly higher in all the gel groups (23 of 80), including placebo, compared with no gel (one of 20) (Fisher exact test P = 0.037). There was no evidence of a dose effect. Safety tests showed no evidence of systemic absorption. CONCLUSION: Although there was no clear explanation for the spotting, DS4% was well tolerated. It was decided to proceed with DS4% in an expanded safety study in Africa but to restrict entry to low-risk HIV-negative women, include a no-gel group, and monitor intermenstrual bleeding closely.     

Condom use and vaginal Y-chromosome detection: the specificity of a potential biomarker

OBJECTIVE: Detection of vaginal Y-chromosome sequences (YCS) may be a useful biomarker to validate sexual behavior reporting in women. We describe the effects of condom use on the detection of vaginal YCS. METHODS: Fifty-six women were asked to abstain from sexual intercourse for 14 days. On day 15, participants were asked to engage in sexual intercourse with their male partners using condoms. Self-collected vaginal swabs were obtained on days 14, 16, and 17. YCS were detected using the Roche LightCycler with the use of positive controls. RESULTS: Fourty-four of 56 women completed the study. Five women (11.4%) had detectable YCS. The overall specificity of the YCS assay with condom use was 92% (95% CI: 80%-98%). Although women who reported receptive oral sex and digital penetration within 48 hours of swab collection had a higher detection rate of YCS [RR 2.3 (95% CI: 1.1-4.6) and 3.6 (95%CI: 1.6-8.5), respectively], the mean concentration of YCS was much less than that associated with unprotected vaginal intercourse (P <0.001) CONCLUSIONS: Condom use during intercourse appears to prevent vaginal YCS detection; this may be a useful biomarker to validate self-reported condom use.     

A pilot study of vaginal flora changes with randomization to cessation of douching

OBJECTIVES: The objectives of this study were to determine whether women who douche regularly would enter a randomized trial of douching cessation or continuation, whether they would adhere to the assigned behavior, and whether there was a dramatic impact on vaginal flora. GOAL: The goal of this study was to determine the feasibility of a large, definitive trial of douching cessation. STUDY DESIGN: Women who douched at least weekly and who had either bacterial vaginosis or normal flora by Gram stain were assigned at random either to continue douching or to stop for 8 weeks. Vaginal Gram stains were obtained every 7 days from each woman. RESULTS: Forty-eight women were randomized. Those assigned to continue reported douching during 77% of study weeks; those assigned to stop denied douching in 94% of weeks. No dramatic differences in flora were observed between women in the continue versus stop groups. CONCLUSION: A large randomized trial of douching cessation is feasible.     

Rectal microbicide acceptability: results of a volume escalation trial

OBJECTIVES: The objectives of this study were to determine what volume of a microbicide placebo gel is acceptable when applied intrarectally before receptive anal intercourse (RAI); and to evaluate responses to properties of the gel, its application, and its use. STUDY DESIGN: HIV-uninfected men who reported unprotected RAI with serodiscordant or unknown-status partners were enrolled in a volume escalation trial. RESULTS: Up to 35 mL of gel with the physical properties of Femglide (transparent and odorless) was acceptable to the majority of participants. Choice of different levels of viscosity may be needed. For some men, volumes judged acceptable when tried without intercourse were not acceptable when used during sex. Overall, participants reported high intentions to use microbicides when available. Condom use was inconsistent despite advice to use condoms. CONCLUSIONS: Microbicides that would require up to 35 mL of volume to be effective would be acceptable to men who engage in high-risk RAI.     

Topical microbicide use by adolescent girls: concerns about timing, efficacy, and safety

BACKGROUND AND OBJECTIVES: Adolescent girls could benefit from topical microbicide use if the product is acceptable to them. GOAL: The goal was to evaluate girls', mothers', experienced healthcare providers', and medical students' views on timing of use, efficacy, and safety of topical microbicide use by adolescents. STUDY DESIGN: Focus groups were conducted with girls, mothers, healthcare providers, and medical students. All groups were videotaped, transcribed, and coded for relevant themes. RESULTS: A delay between insertion and coitus presented a problem, and pre- and postcoital use had advantages depending on the group. Efficacy was evaluated by timing of use, smell, ability to feel the product, and confidence that it would spread sufficiently. There were concerns about physical side effects and the impact on normal vaginal flora. CONCLUSION: This study demonstrated the importance of understanding the unique needs and perspectives of adolescent girls and the adults who have an influence on their use.     

Comparison of vaginal flora after treatment with a clotrimazole 500 mg vaginal pessary or a fluconazole 150 mg capsule for vaginal candidosis.

The effect of antifungal therapy on the vaginal microbial flora was studied in 23 patients suffering from culture-positive, symptomatic vaginal candidosis. They were randomly allocated to receive either a 500 mg clotrimazole vaginal pessary or a 150 mg fluconazole capsule. Quantitative microbiological examination was carried out on samples of vaginal secretions obtained prior, and at intervals up to 10 days after, treatment. No significant difference was found in the vaginal flora before or after therapy in individual patients or between the treatment groups. In patients with C glabrata or C krusei, the yeasts persisted longer in the vagina with poorer response to either of the medications.     

Safety and toxicity of nonoxynol-9 gel as a rectal microbicide

BACKGROUND AND OBJECTIVES: Methods of HIV and STD prevention, which can be controlled by the receptive partner, are a high priority for research and development. Studies on the safety of Nonoxynol-9 (N-9) on the vaginal mucosa have yielded conflicting results. No Phase I study has evaluated the effect of N-9 on the rectal mucosa. GOALS: To assess the safety of 52.5 mg of N-9 in a 1.5-g gel when applied one to four applicators per day to the rectum and penis. STUDY DESIGN: The study included 25 HIV-negative and 10 HIV-positive, monogamous gay male couples in which each partner was exclusively insertive or receptive while using N-9 gel. Each participant served as his own control during placebo gel use compared to during N-9 gel use. Receptive partners underwent anoscopic examination after 1 week of placebo use and after 2, 5, and 6 weeks of N-9 gel use, with rectal biopsies obtained after 1 week of placebo use and after 5 and 6 weeks of N-9 gel use. Insertive partners had safety monitoring after 1 week of placebo use and after 2, 5, and 6 weeks of N-9. RESULTS: No rectal ulcers were detected; superficial rectal erosions were noted in two HIV-negative participants. Abnormal or slightly abnormal histologic abnormalities of rectal biopsies were detected in 31 (89%) receptive participants after N-9 gel use compared to 24 (69%) participants after 1 week of placebo gel use. Meatal ulceration, not caused by herpes simplex virus, was detected in one HIV-negative participant. CONCLUSION: Low-dose N-9 gel was not associated with macroscopic rectal and penile epithelial disruption or inflammation, but histologic abnormalities were commonly observed during N-9 gel as well as during placebo gel use.     

Cutaneous Microflora of Patients with Repeated Skin Infections

The microflora of normal skin in 16 patients with repeated staphylococcal and streptococcal skin infections was examined to determine whether abnormalities existed which would indicate a protective role for the indigenous flora against colonization by pathogens. Five sites-hands, feet, axilla, groin and back-were examined quantitatively and qualitatively and compared with a control group. Total populations of indigenous flora were significantly higher from patients with repeated skin infections of the back, axillae and feet. The frequency of isolation of different species from normal skin was comparable between the control and experimental groups, with the exception of the incidence of Staphylococcus aurcus and Proteus species which were isolated only from patients with repeated skin infections. Gram-negative bacteria were isolated with comparable frequency between the two groups, but patients with repeated skin infections tended to carry gram-negative bacteria on multiple sites. It was concluded from the high population of indigenous flora and the types of microorganisms present that the microflora of normal skin did not appear to protect patients with repeated skin infections against colonization by pathogens. The presence of high populations of Staphylococcus aurcus on the normal skin of patients with repeated skin infections would appear to be the most important contributing factor.     

Assessment of adherence to product dosing in a pilot microbicide study

OBJECTIVES: To determine whether applicator staining could be incorporated into a microbicide study as a marker of adherence. GOAL: To test whether observers could identify intravaginally inserted applicators and compare the observers' ratings to subjects' self reports. STUDY DESIGN: Subjects participating in a 14-day microbicide trial to assess the safety of 0.5% PRO 2000 or matched placebo gel returned used and unused applicators. Each applicator was individually dyed or batched and immersed in a 0.4% trypan blue waterbath. Masked observers rated the applicators as intravaginally inserted or not; results were compared to subjects' self-reports. To determine if the dye would allow observers to differentiate whether applicators had been filled before intravaginal insertion, staff either filled applicators and discarded gel ex vivo or asked volunteers to intravaginally insert applicators without gel and mixed these with a random sampling of used and unused study samples.RESULTS: 358 of 360 applicators were returned; 306 were reported to have been vaginally inserted and 52 unused. Observers agreed with the participant's self reports in 98-99% of cases. No differences were observed between applicators stained individually or in batches. The ability to distinguish between applicators that were presumed to have been used properly, intravaginally inserted without gel, filled with gel and emptied ex vivo, or unused ranged from 76 to 87%. CONCLUSIONS: Staining of applicators is accurate, inexpensive, and correlated well with self-report in a study of short duration. This method could prove useful in assessing adherence to product dosing in future microbicide trials.     

Validation of a simplified grading of Gram stained vaginal smears for use in genitourinary medicine clinics

OBJECTIVES: To validate a simplified grading scheme for Gram stained smears of vaginal fluid for the diagnosis of bacterial vaginosis (BV) against the accepted "gold" standard of Amsel's composite criteria. METHODS: Women attending genitourinary medicine (GUM) clinics, as part of a multicentre study, were diagnosed as having BV if three or more of the following criteria were present; homogeneous discharge, elevated vaginal pH, production of amines, and presence of "clue" cells. Women with less than three of the criteria were considered as normal. Simultaneously, smears were made of vaginal fluid and Gram stained and then assessed qualitatively as normal (grade I), intermediate (grade II), or consistent with BV (grade III). Two new grades were used, grade 0, epithelial cells only with no bacteria, and grade IV, Gram positive cocci only. RESULTS: BV was diagnosed in 83/162 patient visits using the composite criteria, the remainder being regarded as normal. The majority of patients with BV had a smear assessed as grade III (80/83, 96%) and the majority of normal women had a smear assessed as grade I (normal, 48/79, 61%), giving a high sensitivity (97.5%), specificity (96%), and predictive value for a positive (94.1%) and negative (96%) test, kappa index = 0.91. Smears assessed as grade II were found predominantly (12/13) among patients diagnosed as normal, with less than three of the composite criteria. Grades 0 and IV were both only found among normal women. CONCLUSION: This simplified assessment of Gram stained smears can be used as an alternative to Amsel's criteria and is more applicable for use in busy GUM clinics.